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Abstract:

The present invention relates to chemical processes for the manufacture
of certain quinazoline derivatives, or pharmaceutically acceptable salts
thereof. The invention also relates to processes for the manufacture of
certain intermediates useful in the manufacture of the quinazoline
derivatives and to processes for the manufacture of the quinazoline
derivatives utilising said intermediates. In particular, the present
invention relates to chemical processes and intermediates useful in the
manufacture of the compound
4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-
quinazoline.

Claims:

1. A process for the manufacture of a compound of the Formula II
##STR00049## from a compound of Formula III: ##STR00050## wherein
R1 and R2 are independently selected from chlorine, bromine,
fluorine, iodine and optionally substituted alkylsulphonyloxy; which
process comprises the steps of: (a) reacting a compound of Formula III
with an ester of Formula (IV) ##STR00051## in the presence of a
suitable solvent, wherein R3 is a suitable esterifying group; to
form a compound of the Formula V: ##STR00052## (b) reacting a compound
of Formula V with hydroxide ion in the presence of an aryl-alkyl ammonium
salt or a tetra-alkyl ammonium salt to form a compound of Formula VI
##STR00053## (c) reacting a compound of Formula VI in the presence of a
suitable acid to form a compound of Formula VII; ##STR00054## and (d)
reducing the compound of the Formula VII to form a compound of Formula
II.

2. The process according to claim 1, wherein R1 and R2 are both
fluorine.

3. The process according to claim 1, wherein R3 is C1-6alkyl or
benzyl.

4. The process according to claim 1, wherein step (a) is conducted in a
suitable solvent selected from toluene, trimethylbenzene and xylene.

5. The process according to claim 1, wherein step (b) is carried out in
the presence of an aryl-alkyl ammonium salt, which is Triton B.

6. A compound of Formula VI ##STR00055## wherein R3 is an
esterifying group; or salt thereof or protected derivative thereof.

7-20. (canceled)

21. A salt of a compound of Formula XII ##STR00056## wherein the
compound is 1-(3-chloropropyl)pyrrolidine oxalate,

23. A process for the manufacture of a compound of Formula XI-1
##STR00058## wherein A is a suitable ring system from a compound of the
Formula X-1, wherein L1 is a leaving group; ##STR00059## which
comprises (g-2) reacting the compound of the Formula X-1 with a compound
of Formula VII ##STR00060## to form the compound of the Formula
XIV-1: ##STR00061## (i-2) reducing a compound of Formula XIV-1 to form
a compound of Formula XI-1.

24. A process for the manufacture of a compound of Formula XI-1
##STR00062## from a compound of the Formula X-1, wherein L1 is a
leaving group; ##STR00063## which comprises (g-3) reacting the compound
of the Formula X-1 with a compound of Formula VI ##STR00064## to form
the compound of the Formula XIV-2: ##STR00065## (i-2) reducing a
compound of Formula XIV-2 to form a compound of Formula XI-2; and
##STR00066## (j-3) hydrolysing a compound of Formula XI-2 to form a
compound of Formula XI-1.

25. A compound selected from: a compound of Formula XIV; ##STR00067##
wherein R4 is a protecting group; a compound of Formula XIV-1
##STR00068## wherein A is a ring system as defined below; a compound of
Formula XIV-2 ##STR00069## wherein A is a ring system as defined below,
and R3 is a suitable esterifying group; and a compound of Formula
XI-2 ##STR00070## wherein A is a ring system as defined below and
R3 is a suitable esterifying group; wherein ring system A of
compound XIV-1, XIV-2 or XI-2 is selected from any one of the following
ring structures: ##STR00071##

26. A process for the manufacture of a compound of the Formula XI:
##STR00072## from a compound of the Formula IX: ##STR00073## wherein
R4 is a protecting group which process comprises the steps of: (f)
reaction of a compound of Formula IX with a derivatizing agent to form a
compound of Formula X ##STR00074## wherein L1 is a leaving
group; (g-1) reacting the compound of the Formula X with a compound of
Formula VII, ##STR00075## optionally in situ, optionally in the
presence of the solvent used in step (f), to form the compound of the
Formula XIV: ##STR00076## (i-1) reducing a compound of Formula XIV to
form a compound of Formula X1 ##STR00077## and whereafter the compound
of the Formula XI obtained in the form of the free acid may be converted
into a salt form and the compound of the Formula XI obtained in the form
of a salt may be converted into the free acid or into the form of an
alternative salt.

Description:

[0001] This application claims the benefit under 35 U.S.C. §119(e) of
Application No. US 60/864036 filed on 2 Nov. 2006 and Application No. US
60/957401 filed on 22 Aug. 2007.

[0002] The present invention relates to chemical processes for the
manufacture of certain quinazoline derivatives, or pharmaceutically
acceptable salts thereof The invention also relates to processes for the
manufacture of certain intermediates useful in the manufacture of the
quinazoline derivatives and to processes for the manufacture of the
quinazoline derivatives utilising said intermediates.

[0003] In particular, the present invention relates to chemical processes
and intermediates useful in the manufacture of the compound
4-(4-fluoro-2-methylindol-1H-5-yloxy)-6-methoxy-7-[3-(pyrrolidin-1-yl)pro-
poxy]quinazoline. This compound falls within the disclosure of WO 00/47212
and is exemplified in Example 240 therein.

[0004] The compound
4-(4-fluoro-2-methylindol-1H-5-yloxy)-6-methoxy-7-[3-(pyrrolidin-1-yl)pro-
poxy]quinazoline is described herein by way of the Formula I:

[0006] Receptor tyrosine kinases (RTKs) are important in the transmission
of biochemical signals across the plasma membrane of cells. These
transmembrane molecules characteristically consist of an extracellular
ligand-binding domain connected through a segment in the plasma membrane
to an intracellular tyrosine kinase domain. Binding of ligand to the
receptor results in stimulation of the receptor-associated tyrosine
kinase activity which leads to phosphorylation of tyrosine residues on
both the receptor and other intracellular molecules. These changes in
tyrosine phosphorylation initiate a signalling cascade leading to a
variety of cellular responses. To date, at least nineteen distinct RTK
subfamilies, defined by amino acid sequence homology, have been
identified. One of these subfamilies is presently comprised by the
fms-like tyrosine kinase receptor, Flt-1 (also referred to as VEGFR-1),
the kinase insert domain-containing receptor, KDR (also referred to as
VEGFR-2 or Flk-1), and another fms-like tyrosine kinase receptor, Flt-4.
Two of these related RTKs, Flt-1 and KDR, have been shown to bind VEGF
with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et
al, 1992, Biochem. Biophys. Res. Comm 1992, 187: 1579-1586). Binding of
VEGF to these receptors expressed in heterologous cells has been
associated with changes in the tyrosine phosphorylation status of
cellular proteins and calcium fluxes.

[0011] WO 02/12227 discloses several possible routes for preparing
indoleoxy bicyclic compounds. However, there is no specific disclosure in
WO 02/12227 of a process for preparing a compound of the Formula I.

[0012] WO 00/47212 discloses a route for the preparation of a compound of
Formula I (see Example 240). This route for preparing the compound of the
Formula I is satisfactory for the synthesis of relatively small amounts
of the compound. However, the route involves linear rather than
convergent synthesis, requiring the use of multiple purification steps
and the isolation of a substantial number of intermediates. As such, the
overall yield of the synthesis is not high. There is, therefore, a need
for a more efficient synthesis of the compound of the Formula I suitable
to make larger quantities of that compound. There is also a need for more
efficient syntheses of the intermediate compounds useful in the synthesis
of the compound of the Formula I to make larger quantities of those
intermediate compounds.

[0013] Preferably, the new syntheses should minimise the number of
intermediate compounds that need to be isolated and should not involve
costly and time-consuming purification procedures. Additionally, the new
syntheses should form consistently high quality compounds, in particular
so as to form a high quality compound of the Formula I to satisfy the
high purity requirements of a pharmaceutical product. The new syntheses
should also use procedures and reagents that can safely be used in a
manufacturing plant and that meet environmental guidelines.

[0014] According to the present invention, we now provide improved
processes for the manufacture of AZD2171, the compound of the Formula I.

[0015] According to the present invention, processes are also provided for
the manufacture of key intermediate compounds that may be used in the
manufacture of AZD2171.

[0016] The new processes are advantageous in that they allow the compounds
to be made in high quality and high yield on a larger scale. The
processes allow a substantial reduction in the number of intermediate
compounds that must be isolated and, in general, are more convergent than
the previous routes. Such changes provide significant advantages of time
and cost.

[0017] For the avoidance of doubt, the term "AZD2171" as used hereinafter
refers to the AZD2171 free base, unless otherwise stated.

[0018] A key intermediate that may be used in the preparation of AZD2171
is 2-methyl-4-fluoro-5-hydroxy-indole, the compound of the Formula II:

##STR00002##

[0019] Example 237 of WO 00/47212 discloses three routes for the
preparation of a compound of the Formula II. [0020] (i) The first route
involves the reaction of 2-fluoro-4-nitroanisole with
4-chlorophenoxyacetonitrile in dimethylformamide (DMF) solvent in the
presence of potassium tert-butoxide followed by reduction with hydrogen
using a palladium on charcoal catalyst to give a mixture of
4-fluoro-5-methoxyindole and 6-fluoro-5-methoxyindole. After protection
of the indole nitrogen with tert-butoxycarbonyl, the mixture of protected
indoles is reacted in tetrahydrofuran (THF) solvent with
tert-butyllithium and methyl iodide followed by trifluoroacetic acid to
give a mixture of 6-fluoro-5-methoxy-2-methyl-indole and
4-fluoro-5-methoxy-methylindole. After purification the
4-fluoro-5-methoxy-methylindole is reacted with boron tribromide in
methylene chloride to give the compound of Formula II,
4-fluoro-5-hydroxy-2-methylindole. [0021] (ii) The second route involves
the reaction of ethyl acetoacetate with 1,2,3-trifluoro-4-nitrobenzene in
THF in the presence of sodium hydride to form
3-acetylmethyl-1,2-difluoro-4-nitrobenzene.
3-Acetylmethyl-1,2-difluoro-4-nitrobenzene is then reacted with trimethyl
orthoformate in methylene chloride in the presence of montmorillonite to
form 1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene.
1,2-Difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene is then reacted with
benzyl alcohol in dimethylacetamide (DMA) in the presence of sodium
hydride to form 3-acetylmethyl-1-benzyloxy-2-fluoro-4-nitrobenzene. This
compound is cyclized and deprotected by reacting with 10% palladium on
charcoal in ethanol/acetic acid in the presence of hydrogen to give the
compound of Formula II, 4-fluoro-5-hydroxy-2-methylindole. [0022] (iii)
The third route involves the reaction of
1,2-difluoro-3-(2,2-dimethoxypropyl)-4-nitrobenzene with sodium methoxide
in methanol to give 3-acetylmethyl-2-fluoro-1-methoxy-4-nitrobenzene.
This compound is cyclized and deprotected by reacting with titanium
trichloride in acetone in the presence of ammonium acetate to give the
4-fluoro-5-methoxy-2-methylindole. The 4-fluoro-5-methoxy-methylindole is
then reacted with boron tribromide in methylene chloride to give the
compound of Formula II, 4-fluoro-5-hydroxy-2-methylindole.

[0023] The routes disclosed in the prior art documents for the preparation
of a compound of the Formula II are satisfactory for the synthesis of
relatively small amounts of the compound. However, they all require each
of the intermediates to be isolated and, therefore, include multiple
isolation and/or purification steps. This results in a satisfactory
overall yield of the compound of the Formula II on the small scale used.
However, the routes disclosed in the prior art documents are unsuitable
for use on a manufacturing scale because they include multiple isolation
and/or purification steps, which cannot be conducted efficiently on a
manufacturing scale. In particular, the routes disclosed in the prior art
documents are unsuitable for use in the manufacture of a high purity
pharmaceutical product.

[0024] There is, therefore, a need for a more efficient synthesis of a
compound of the Formula II suitable for use to make larger quantities of
that compound. Preferably, the new synthesis should not involve costly
and time-consuming isolation and/or purification procedures. Thus, the
new synthesis should reduce the number of isolation and/or purification
procedures required, thereby reducing costs and time of manufacture.
Preferably, the new synthesis should minimise the number of solvents used
throughout the process, which improves environmental performance and
provides the opportunity for solvent recovery. Preferably, the new
synthesis should also provide a robust and reliable method of isolating
the compound of the Formula II and consistently should provide high
quality compound of the Formula II, for example so as to satisfy the
regulatory requirements for the introduction of starting materials into
the production of pharmaceutical products.

[0025] International patent application, publication number WO 2004/009542
discloses an alternative method for making
2-methyl-4-fluoro-5-hydroxy-indole.

[0026] According to a first aspect of the present invention, there is
provided a process for the manufacture of a compound of the Formula II
from a nitrobenzene derivative of Formula III:

##STR00003## [0027] wherein R1 and R2 are independently
selected from fluorine, chlorine, bromine, iodine and optionally
substituted alkylsulphonyloxy such as trifloxy or tosyloxy; [0028] which
process comprises the steps of: [0029] (a) reacting a compound of Formula
III with an ester of Formula (IV)

[0029] ##STR00004## [0030] wherein R3 is a suitable esterifying
group; [0031] to form a compound of the Formula V:

[0031] ##STR00005## [0032] (b) reacting a compound of Formula V with
hydroxide ion in the presence of an aryl-alkyl ammonium salt or a
tetra-alkyl ammonium salt to form a compound of Formula VI

[0032] ##STR00006## [0033] (c) reacting a compound of Formula VI to
form a compound of Formula VII;

[0033] ##STR00007## [0034] (d) reduction of the compound of the Formula
VII to form a compound of Formula II.

[0035] In one embodiment R1 and R2 are independently selected
from fluorine, chlorine, bromine and iodine. In another embodiment
R1 and R2 are independently selected from fluorine, chlorine
and bromine In another embodiment R1 is fluorine and R2 is
bromine In another embodiment both R1 and R2 are fluorine.

[0036] R3 is a suitable esterifying group such as optionally
substituted C1-6alkyl or optionally substituted benzyl. The skilled
person would be able to select suitable esterifying groups which would
not interfere with the processes of this embodiment of the invention and
would allow removal of the ester group during process step (c).

[0037] In one embodiment R3 is C1-6alkyl or benzyl. In another
embodiment C1-6alkyl. In another embodiment R3 is
C1-4alkyl. In a further embodiment R3 is C4alkyl,
conveniently tert-butyl.

Reaction Conditions for Process (a)

[0038] The reaction of process (a) is conveniently carried out in the
presence of a suitable solvent such as tetrahydrofuran or acetonitrile or
in another embodiment a suitable non-polar solvent, such as toluene,
trimethylbenzene or xylene, in the presence of a suitable base such as
sodium t-butoxide or sodium tert-pentoxide. In another embodiment the
non-polar solvent is selected from toluene or trimethylbenzene.

[0039] The reaction of step (a) is carried out at a temperature in the
range, for example, of from 50 to 110° C., conveniently in the
range of from 60 to 80° C., more conveniently in the range of from
65 to 75° C.

[0040] The compound of Formula IV may conveniently be selected from methyl
3-oxobutanoate, ethyl 3-oxobutanoate, propyl 3-oxobutanoate, butyl
3-oxobutanoate, sec-butyl 3-oxobutanoate and t-butyl 3-oxobutanoate.
Alternatively the compound of Formula IV may be selected from methyl
3-oxobutanoate, ethyl 3-oxobutanoate and t-butyl 3-oxobutanoate.
Conveniently t-butyl 3-oxobutanoate can be used since this requires
milder reaction conditions to be used in the process which has the
advantage that the reactions are easier to perform and lower levels of
side products are produced.

Reaction Conditions for Process (b)

[0041] The reaction of process (b) is conveniently carried out in a
suitable solvent such as water or a water miscible solvent such as
tetrahydrofuran or acetonitrile in the presence of a suitable base such
as sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0042] The reaction of step (b) is carried out at a temperature in the
range, for example, of from 30 to 70° C., conveniently in the
range of from 40 to 60° C., more conveniently in the range of from
45 to 55° C.

[0044] The reaction of process (c) is conveniently carried out in a
suitable solvent, such as dichloromethane in the presence of an acid,
such as trifluoroacetic acid or toluene in the presence of an acid, such
as para-toluene sulphonic acid, acetic acid, propionic acid or a mixture
of acetic acid and sulphuric acid.

[0045] When trifluoroacetic acid in dichloromethane is used the reaction
of step (c) is carried out at a temperature in the range, for example, of
from 0 to 40° C., conveniently in the range of from 10 to
35° C., more conveniently in the range of from 20 to 30° C.
When toluene is used in the presence of para-toluene sulphonic acid,
acetic acid, propionic acid or a mixture of acetic acid and sulphuric
acid the reaction of step (c) is carried out a temperature in the range
of between 80° C. and the boiling point of the solvent/acid
mixture. In one embodiment the temperature is 90° C.

Reaction Conditions for Process (d)

[0046] The skilled practitioner will be familiar with a number of methods
suitable for the reduction of a compound of Formula VII. For example
sodium dithionite or hydrogen gas in the presence of a suitable catalyst
such as palladium on charcoal. When sodium dithionite is used the
reaction of process (d) is conveniently carried out in a suitable solvent
such as water or a water miscible solvent such as tetrahydrofuran,
acetonitrile or an alcohol for example methanol, ethanol or isopropanol
advantageously in the presence of a suitable base such as potassium
carbonate or sodium carbonate. For further examples the reader is
referred to Comprehensive Organic Transformations" by Richard C. Larock,
published by John Wiley and Sons, 2nd Edition which is incorporated
herein by reference.

[0047] The reaction of step (d) is carried out at a temperature in the
range, for example, of from 0 to 50° C., conveniently in the range
of from 10 to 40° C., more conveniently in the range of from 20 to
30° C.

[0048] The process of the first aspect of the present invention is
advantageous in that it allows a compound of the Formula II to be made in
high quality and high yield on a larger scale.

[0049] The steps (a) to (c) can optionally be conducted as a continuous
process without isolation and/or purification of the intermediate
compounds of the Formulae V and VI. This significantly reduces the time
and cost of manufacturing the compound of the Formula II on a larger
scale.

[0050] In one aspect, the process for the manufacture of a compound of the
Formula II may further include the step (e) of isolating and/or purifying
the compound of the Formula II. The step (e) may comprise any suitable
steps or procedures for isolating the desired product that are described
in the literature and/or that are known to the skilled person. Particular
steps that would be of use would provide high quality and high purity
product.

[0051] The step (e) may, for example, also comprise crystallisation using
a suitable solvent system. An example of a suitable solvent system is a
solvent system comprising dissolving the product in dichloromethane and
crystallisation by the addition of isohexane or isoheptane, which
provides a compound of the Formula II in a high purity, typically in a
purity of greater than 90%, conveniently greater than 98%.

[0052] In another aspect of the invention there is provided a compound of
Formula VI or a salt thereof or a protected derivative thereof. Examples
of protected derivatives include compounds wherein the hydroxy group is
replaced by C1-6alkoxy or aryloxy.

[0053] Another key intermediate that may be used in the preparation of
AZD2171 is the compound of the Formula VIII:

##STR00008##

wherein R4 is a protecting group.

[0054] Example 7 of WO 03/064413 discloses a route for the preparation of
a compound of the Formula VIII wherein R4 is benzyl. The route
involves the reaction of 7-benzyloxy-4-chloro-6-methoxyquinazoline free
base with 4-fluoro-5-hydroxy-2-methylindole and potassium carbonate in a
N-methyl pyrrolidinone as solvent to provide the compound of the Formula
VIII. It is stated in Example 7 of WO 03/064413 that
7-benzyloxy-4-chloro-6-methoxyquinazoline was prepared from
7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one by reaction with
thionyl chloride in dimethylformamide as solvent.

[0055] The routes disclosed in the prior art documents for the preparation
of a compound of the Formula VIII are satisfactory for the synthesis of
relatively small amounts of the compound. However, they all require the
isolation and/or purification of intermediate compounds. This results in
a satisfactory, but not high, overall yield of the compound of the
Formula VIII.

[0056] There is, therefore, a need for a more efficient synthesis of a
compound of the Formula VIII suitable for use to make larger quantities
of that compound. Preferably, the new synthesis should not involve costly
and time-consuming isolation and/or purification procedures. Thus, the
new synthesis should reduce the number of isolation and/or purification
procedures required, thereby reducing costs and time of manufacture. The
new synthesis should conveniently also allow for effective isolation of
the compound of the Formula VIII in a crystalline form in high purity and
yield, which crystalline form should have good filtration
characteristics.

[0057] According to a second aspect of the present invention, there is
provided a process for the manufacture of a compound of the Formula VIII:

##STR00009## [0058] wherein R4 is a protecting group [0059] from a
compound of the Formula IX:

[0059] ##STR00010## [0060] which process comprises the steps of: [0061]
(f) reaction of a compound of Formula IX with a derivatizing agent to
form a compound of Formula X [0062] wherein L1 is a leaving group;
and

[0062] ##STR00011## [0063] (g) reacting the compound of the Formula X
with a compound of Formula II (2-methyl-4-fluoro-5-hydroxy-indole)
optionally in situ and optionally in the presence of the solvent used in
step (f) to form the compound of the Formula VIII.

[0064] The term `protecting group` refers to groups which are readily
removed under mild acidic conditions, neutral conditions or mild basic
conditions. Suitable methods for protection are those known to those
skilled in the art. Conventional protecting groups may be used in
accordance with standard practice (for illustration see T. W. Green,
Protective Groups in Organic Synthesis, John Wiley and Sons, 1991).
Suitable protecting groups at R4 include benzyl, substituted benzyl
(for example C1-4alkoxybenzyl, di-alkoxybenzyl, alkylbenzyl and
di-C1-4alkybenzyl), tert-butyl, 1, 1-dimethyl-1-ethylmethyl, allyl,
substituted allyl (such as C1-4alkylallyl) or methoxyethoxymethyl.
In another embodiment R4 is benzyl.

[0065] For the avoidance of doubt the term `in situ` means that the
reaction was performed without isolation of the products from the
previous process step.

[0066] The process of the second aspect of the invention is advantageous
in that it allows a compound of the Formula VIII to be made in high
purity and high yield on a larger scale.

[0067] The derivatizing agent could comprise any suitable agent for
inserting a leaving group at the 4 position of the compound of Formula
IX. Examples of L1 include chlorine, bromine, is iodine and
optionally substituted alkylsulphonyl such as triflyl and tosyl. Examples
of derivatizing agents include a chlorinating agent (such as phosphorus
oxychloride), a brominating agent (such as phosphorus oxybromide or a
mixture of N-bromosuccinimide and tri-isopropyl phosphite) and an
iodinating agent.

[0068] When the derivatizing agent is a chlorinating, brominating or
iodinating agent the process step (f) could comprise: [0069] (f) reacting
the compound of the Formula IX with a suitable derivatizing agent in the
presence of a suitable base and a suitable solvent, wherein the reaction
is carried out by: [0070] (f-1) adding a mixture of the compound of the
Formula IX and the base in the solvent to a mixture of the derivatizing
agent in the solvent at a temperature in the range of from 60 to
110° C. over a period of about 60 minutes; or [0071] (f-2) adding
the derivatizing agent to a mixture of the compound of the Formula IX and
the base in the solvent at ambient temperature over a period of about 15
minutes and then heating the reaction mixture over a period of about 90
minutes to a temperature in the range of from 70 to 90° C. and
stirring the reaction mixture at that temperature for about 1 hour; or
[0072] (f-3) adding the derivatizing agent to a mixture of the compound
of the Formula IX and the base in the solvent at a temperature in the
range of from 60 to 110° C. over a period of about 15 minutes,

[0073] A suitable solvent in step (f) is selected from toluene,
chlorobenzene, 1,2-dimethoxyethane, acetonitrile and anisole. In one
embodiment the solvent is anisole or toluene. In another embodiment the
solvent is anisole.

[0074] A suitable solvent in step (g) is selected from toluene,
chlorobenzene, 1,2-dimethoxyethane and anisole. In one embodiment the
solvent is anisole or toluene. In another embodiment the solvent is
anisole.

[0075] A co-solvent or co-solvents may be required to be added to solvents
in (f) and (g) for example to aid solubility of the chlorobenzyline or
indole intermediates. For example anisole can optionally comprise
acetonitrile and N-methyl pyrolidinone and 1,2-dimethoxyethane can
comprise N-methyl pyrolidinone.

[0076] In one aspect of the invention, steps (f) and (g) are conducted in
toluene as the solvent.

[0077] In another aspect of the invention, steps (f) and (g) are conducted
in anisole as the solvent.

[0078] The product of step (f) need not be isolated before conducting the
step (g). This allows the process to be conducted as a continuous process
without isolation and/or purification of the intermediate compound of the
Formula X. This significantly reduces the time and cost of manufacturing
the compound of the Formula VIII on a larger scale. The use of anisole as
the reaction solvent is advantageous because this solvent minimise the
formation of by-products. The choice of solvent also allows for the easy
and convenient isolation of the compound of the Formula VIII. For
example, when the reaction mixture is cooled to ambient temperature, the
compound of the Formula VIII typically forms a solid, which solid may
then be collected by any conventional method.

[0079] The mode of addition of the reagents in step (f) (i.e. as described
in steps (f-1), (f-2) and (f-3)) is advantageous because it minimises the
formation of by-products/impurities in that step. Reducing the formation
of by-products/impurities enables the intermediate compound of the
Formula X produced in step (f) to be used in step (g) without isolation
and/or purification. Reducing the formation of by-products/impurities in
step (f) also allows for the correct stoichiometry of the reagents in
step (g) of the process and, therefore, a more efficient reaction in that
step. This is turn provides a high yield and high purity of the compound
of the Formula IX in step (g).

[0080] A suitable chlorinating agent for use in step (f) is phosphorus
oxychloride. Typically, in step (f), a molar excess of chlorinating agent
is used relative to the compound of the Formula IX. For example, a molar
excess in the range of from 1 to 2.0, conveniently in the range of from
1.2 to 1.4, may be used.

[0081] A suitable base for use in step (f) is a base selected from
triethylamine and N,N-diisopropylethylamine. In particular, the base is
diisopropyethylamine. Adding a source of chloride to the reaction mixture
(such as, for example, triethylamine hydrochloride) may reduce the
formation of by-products.

[0082] In step (f-1), the reaction is carried out at a temperature in the
range of from 60 to 80° C., conveniently in the range of from 65
to 75° C., more conveniently in the range of from 70 to 75°
C.

[0083] In step (f-2), the addition of reagents is carried out at ambient
temperature. By the term "ambient temperature" we mean a temperature in
the range of from -10 to 30° C., especially a temperature in the
range of from 10 to 20° C., more especially a temperature of about
15° C. The reaction mixture is then heated to a temperature in the
range of from 70 to 90° C., conveniently in the range of from 75
to 85° C., more conveniently in the range of from 80 to 85°
C.

[0084] In step (f-3), the reaction is carried out at a temperature in the
range of from 70 to 90° C., conveniently in the range of from 75
to 85° C., more conveniently in the range of from 80 to 85°
C.

[0085] In step (f), the term "of about" is used in the expressions "of
about 60 minutes", "of about 15 minutes", "of about 90 minutes and "of
about 1 hour" to indicate that the time periods quoted should not be
construed as being absolute values because, as will be appreciated by
those skilled in the art, the time periods may vary slightly. For
example, the time periods quoted may vary by ±50%, particularly by
±15%, particularly by ±10% from the values quoted in step (f).

[0086] In one aspect of the invention, following step (f) of the process,
the compound of the Formula X is isolated and/or purified, for example
before storage, handling and/or further reaction. Therefore, in one
aspect of the invention, the process for manufacturing a compound of the
Formula X further includes the step of isolating the compound of the
Formula X. The step may comprise any suitable steps or procedures for
isolating the desired product that are described in the literature and/or
that are known to the skilled person. Particular steps that would be of
use would provide high quality and high purity product.

[0087] The reaction of step (g) is carried out at a temperature in the
range of from 60 to 85° C., conveniently in the range of from 65
to 80° C., more conveniently in the range of from 70 to 75°
C.

[0088] In one aspect of the invention, following step (g) of the process,
the compound of the Formula VIII is isolated and/or purified, for example
before storage, handling and/or further reaction. Therefore, in one
aspect of the invention, the process for manufacturing a compound of the
Formula VIII further includes the step (h) of isolating the compound of
the Formula VIII. The step (h) may comprise any suitable steps or
procedures for isolating the desired product that are described in the
literature and/or that are known to the skilled person. Particular steps
that would be of use would provide high quality and high purity product.
The reaction mixture may be cooled to ambient temperature, at which
temperature the compound of the Formula VIII typically forms a solid, and
the solid so formed may be collected by any conventional method, for
example by filtration.

[0089] Both the compounds of the Formula IX and the nitrobenzene
derivative of Formula III starting material are commercially available or
can be prepared using conventional methods. For example the compound of
Formula IX may be prepared as described in Example 5, preparation of
starting materials.

[0090] Another key intermediate that may be used in the preparation of
AZD2171 is
7-hydroxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, the
compound of the Formula XI:

##STR00012##

[0091] Example 7 of WO 03/064413 discloses a route for the preparation of
a compound of the Formula XI. The route involves the reaction of
7-benzyloxy-4-(2-methyl-4-fluoroindol-5-yloxy)-6-methoxyquinazoline (a
compound of Formula VIII) with ammonium formate in dimethylformamide
containing 10% palladium on carbon to give a compound of Formula XI.

[0092] This route disclosed in the prior art for the preparation of a
compound of the Formula XI is satisfactory for the synthesis of
relatively small amounts of the compound. However, it requires the
isolation and/or purification of intermediate compounds. This results in
a satisfactory, but not high, overall yield of the compound of the
Formula XI.

[0093] There is, therefore, a need for a more efficient synthesis of the
compound of the Formula XI suitable for use to make larger quantities of
that compound. Preferably, the new synthesis should not involve costly
and time-consuming purification procedures. Thus, the new synthesis
should reduce the number of isolation and/or purification procedures
required, thereby reducing costs and time of manufacture. Preferably, the
new synthesis should minimise the number of solvents used throughout the
process, which improves environmental performance and provides the
opportunity for solvent recovery. The new synthesis should also enable
effective crystallisation of the compound of the Formula XI in a
crystalline form with good filtration characteristics and in high purity
and yield.

[0094] According to a third aspect of the present invention, there is
provided a process for the manufacture of
7-hydroxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, a
compound of the Formula XI:

##STR00013## [0095] from a compound of the Formula IX:

[0095] ##STR00014## [0096] wherein R4 is a protecting group [0097]
which process comprises the steps of: [0098] (f) reaction of a compound
of Formula IX with a derivatizing agent to form a compound of Formula X
[0099] wherein L1 is a leaving group;

[0099] ##STR00015## [0100] (g) reacting the compound of the Formula X
with a compound of Formula II (2-methyl-4-fluoro-5-hydroxy-indole),
optionally in situ,optionally in the presence of the solvent used in step
(f) to form a compound of the Formula VIII;

##STR00016##

[0100] and [0101] (i) removing R4 from the compound of the Formula
VIII to form the compound of the Formula XI or a salt thereof;

[0102] and whereafter the compound of the Formula XI obtained in the form
of the free base may be converted into a salt form and the compound of
the Formula XI obtained in the form of a salt may be converted into the
free base or into the form of an alternative salt, if necessary.

[0103] When the derivatizing agent is a chlorinating, brominating or
iodinating agent the process step (f) could comprise: [0104] (f) reacting
the compound of the Formula IX with a suitable derivatizing agent in the
presence of a suitable base and a suitable solvent, wherein the reaction
is carried out by: [0105] (f-1) adding a mixture of the compound of the
Formula IX and the base in the solvent to a mixture of the derivatizing
agent in the solvent at a temperature in the range of from 60 to
110° C. over a period of about 60 minutes; or [0106] (f-2) adding
the derivatizing agent to a mixture of the compound of the Formula IX and
the base in the solvent at ambient temperature over a period of about 15
minutes and then heating the reaction mixture over a period of about 90
minutes to a temperature in the range of from 70 to 90° C. and
stirring the reaction mixture at that temperature for about 1 hour; or
[0107] (f-3) adding the derivatizing agent to a mixture of the compound
of the Formula IX and the base in the solvent at a temperature in the
range of from 60 to 110° C. over a period of about 15 minutes,

[0108] The process of the third aspect of the invention is advantageous in
that it allows the compound of the Formula XI to be made in high purity
and high yield on a larger scale.

Reaction Conditions for Process (i)

[0109] The reaction of step (i) is carried out at a temperature in the
range of from 20 to 60° C., more conveniently in the range of from
35 to 45° C.

[0110] In one aspect of the invention the reduction of the compound of
Formula VIII is performed by catalytic hydrogenation, for example using
hydrogen gas and an appropriate catalyst such as palladium on carbon.

[0111] In another aspect of the invention the reduction of the compound of
Formula VIII is performed by catalytic transfer hydrogenation, using for
example a non-gaseous hydrogen donor such as cyclohexene or ammonium
formate and an appropriate catalyst such as palladium on carbon.

[0113] In one aspect of the invention, following step (i) of the process,
the compound of the Formula XI is isolated and/or purified. Any suitable
steps or procedures for isolating and/or purifying the desired product
that are described in the literature and/or that are known to the skilled
person may be used. Particular steps that would be of use would provide
high quality and high purity product. For example the compound of Formula
XI may be isolated from NMP by addition of an antisolvent such as water,
methanol, ethanol, isopropanol, butanol or acetonitrile.

[0114] In another embodiment of the invention, following the process (i),
the compound of Formula XI is used in situ in the next step in the
process.

[0115] According to a further embodiment of the third aspect of the
invention there is provided a process for the manufacture of a compound
of Formula XI from a compound of Formula X comprising the process steps
(g) and (i) above.

[0116] According to a further embodiment of the third aspect of the
invention there is provided a process for the manufacture of
7-hydroxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, a
compound of the Formula XI:

##STR00017## [0117] is from a compound of the Formula IX:

[0117] ##STR00018## [0118] wherein R4 is a protecting group [0119]
which process comprises the steps of: [0120] (f) reaction of a compound
of Formula IX with a derivatizing agent to form a compound of Formula X
[0121] wherein L1 is a leaving group;

[0121] ##STR00019## [0122] (g-1) reacting the compound of the Formula X
with a compound of Formula VII,

[0122] ##STR00020## [0123] optionally in situ, optionally in the
presence of the solvent used in step (f), to form the compound of the
Formula XIV:

[0123] ##STR00021## [0124] (i-1) reducing a compound of Formula XIV to
form a compound of Formula XI

##STR00022##

[0124] Reaction Conditions for Process (f)

[0125] Reaction conditions for step (f) are as described above.

[0126] The derivatizing agent could comprise any suitable agent for
inserting a leaving group at the 4 position of the compound of Formula
IX. Examples of L1 include chlorine, bromine, iodine and optionally
substituted alkylsulphonyl such as triflyl and tosyl. Examples of
derivatizing agents include a chlorinating agent (such as phosphorus
oxychloride), a brominating agent (such as phosphorus oxybromide or a
mixture of N-bromosuccinimide and tri-isopropyl phosphite) and an
iodinating agent.

[0127] R4 is a protecting group as defined above.

Reaction Conditions for Process (g-1)

[0128] The reaction of step (g-1) is carried out by addition of a solution
of a salt of a compound of the Formula VII to a solution of a compound of
the Formula X in the solvent used in step (f-1). The salt of a compound
of the Formula VII may be prepared by use of lithium hydroxide, potassium
hydroxide, sodium hydroxide, lithium carbonate, potassium carbonate,
sodium carbonate or cesium carbonate. Optimally sodium hydroxide is used.
The salt is formed at a temperature of -20° C. to +20° C.,
more conveniently in the range -10° C. to 0° C. The
solution of the salt of a compound of the Formula VII is added to a
solution of a compound of the Formula X in the solvent used in step (f-1)
at a temperature of 60° C. to 100° C., conveniently in the
range 70-90° C.

Reaction Conditions for Process (i-1)

[0129] The reaction of step (i-1) is carried out at a temperature in the
range of from 20 to 60° C., more conveniently in the range of from
35 to 45° C.

[0130] In one aspect of the invention the reduction of the compound of
Formula XIV is performed by catalytic hydrogenation, for example using
hydrogen gas and an appropriate catalyst such as palladium on carbon.

[0131] In another aspect of the invention the reduction of the compound of
Formula XIV is performed by catalytic transfer hydrogenation, using for
example a non-gaseous hydrogen donor such as cyclohexene or ammonium
formate and an appropriate catalyst such as palladium on carbon.

[0133] In one aspect of the invention, following step (i-1) of the
process, the compound of the Formula XI is isolated and/or purified. Any
suitable steps or procedures for isolating and/or purifying the desired
product that are described in the literature and/or that are known to the
skilled person may be used. Particular steps that would be of use would
provide high quality and high purity product. For example the compound of
Formula XI may be isolated from NMP by addition of an antisolvent such as
water, methanol, ethanol, isopropanol, butanol or acetonitrile.

[0134] In another embodiment of the invention, following the step (i-1),
the compound of Formula XI is used in situ in the next step in the
process.

[0135] According to a further embodiment of the third aspect of the
invention there is provided a process for the manufacture of a compound
of Formula XI from a compound of Formula X comprising the process steps
(g-1) and (i-1) above.

[0136] In a further embodiment of the invention there is provided a
compound of Formula XIV.

[0137] The further embodiment of the third aspect of the invention is
applicable to the preparation of a number of ring systems substituted by
4-fluoro-2-methylindol-5-yloxy. Thus according to this further embodiment
there is provided a process for the manufacture of a compound of Formula
XI-1

##STR00023## [0138] wherein A is a suitable ring system [0139] from a
compound of the Formula X-1, wherein L1 is a leaving group;

[0139] ##STR00024## [0140] which comprises: [0141] (g-2) reacting the
compound of the Formula X-1 with a compound of Formula VII

[0141] ##STR00025## [0142] to form the compound of the Formula XIV-1:

[0142] ##STR00026## [0143] (i-2) reducing a compound of Formula XIV-1
to form a compound of Formula XI-1

##STR00027##

[0144] Suitable rings systems for ring A are rings capable of being
activated to allow displacement of the activating group by a phenolate
ion, i.e. the structure of Formula VII. Such ring systems include:

##STR00028##

[0145] In one embodiment ring A is selected from quinazoline, quinoline,
cinnoline and pyrrolotriazine. In another embodiment ring A is
quinazoline. In another embodiment ring A is pyrrolotriazine. In another
embodiment ring A is quinazoline and L1 is at the 4-position of the
quinazoline ring. In another embodiment ring A is pyrrolotriazine and
L1 is at the 4-position of the pyrrolotriazine ring.

[0146] Examples of L1 include chlorine, bromine, iodine and
optionally substituted alkylsulphonyloxy or arylsulphonyloxy such as
triflyloxy and p-tosyloxy.

[0149] The skilled person would understand that ring system A could be
substituted by one or more groups. Such groups may be unaffected by the
processes in this embodiment of the invention or may require protecting
during the processes of this embodiment. The skilled man would be
familiar with strategies to protect such group such as the use of
protecting groups, the use of gentler reaction conditions which still
facilitate the processes of the embodiment and/or the use of alternative
catalysts. Conventional protecting groups may be used in accordance with
standard practice (for illustration see T. W. Green, Protective Groups in
Organic Synthesis, John Wiley and Sons, 1991) as described above.

[0150] In one aspect of the invention, following step (i-2) of the
process, the compound of the Formula XI-1 is isolated and/or purified.
Any suitable steps or procedures for isolating and/or purifying the
desired product that are described in the literature and/or that are
known to the skilled person may be used. Particular steps that would be
of use would provide high quality and high purity product.

[0151] In another embodiment of the invention, following the step (i-2),
the compound of Formula XI-1 is used in situ in the next step in the
process.

[0152] A further embodiment of the invention provides a process for the
manufacture of a compound of Formula XI-1 from a compound of Formula X-1
comprising the process steps (g-2) and (i-2) above.

[0153] In a further embodiment of the invention there is provided a
compound of Formula XIV-1.

[0154] Minor variants to the above process are also included within the
ambit of the invention. An example is where a compound of Formula VI,

##STR00029## [0155] wherein R3 is a suitable esterifying group as
defined above, for example C1-6alkyl or benzyl, is used in the place
of a compound of Formula VII in process (g-2). Thus according to this
further embodiment there is provided a process for the manufacture of a
compound of Formula XI-1

[0155] ##STR00030## [0156] from a compound of the Formula X-1, wherein
L1 is a leaving group;

[0156] ##STR00031## [0157] which comprises [0158] (g-3) reacting the
compound of the Formula X-1 with a compound of Formula VI

[0158] ##STR00032## [0159] to form the compound of the Formula XIV-2:

[0159] ##STR00033## [0160] (i-2) reducing a compound of Formula XIV-2
to form a compound of Formula XI-2

[0160] ##STR00034## [0161] (j-3) hydrolysing a compound of Formula XI-2
to form a compound of Formula XI-1.

##STR00035##

[0162] Examples of L1 include chlorine, bromine, iodine and
optionally substituted alkylsulphonyl such as triflyl and tosyl.

[0165] The reaction of process (J-3) is conveniently carried out in a
suitable solvent such as water or a water miscible solvent such as
tetrahydrofuran or acetonitrile in the presence of a suitable base such
as sodium hydroxide, potassium hydroxide or lithium hydroxide.

[0166] The reaction of step (J-3) is carried out at a temperature in the
range, for example, of from 30 to 70° C., conveniently in the
range of from 40 to 60° C., more conveniently in the range of from
45 to 55° C.

[0168] In one aspect of the invention, following step (j-3) of the
process, the compound of the Formula XI-1 is isolated and/or purified.
Any suitable steps or procedures for isolating and/or purifying the
desired product that are described in the literature and/or that are
known to the skilled person may be used. Particular steps that would be
of use would provide high quality and high purity product.

[0169] In another embodiment of the invention, following the step (j-3),
the compound of Formula XI-1 is used in situ in the next step in the
process.

[0170] A further embodiment of the invention provides a process for the
manufacture of a compound of Formula XI-1 from a compound of Formula X-1
comprising the process steps (g-3), (i-3) and (j-3) above.

[0171] In a further embodiment of the invention there are provided
compounds of Formula XIV-2 and Formula XI-2.

[0172] According to a fourth aspect of the present invention, there is
provided a process for the manufacture of
7-hydroxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline, a
compound of the Formula XI:

##STR00036## [0173] from a compound of the Formula IX:

[0173] ##STR00037## [0174] wherein R4 is a protecting group [0175]
which process comprises the steps of: [0176] (f) reaction of a compound
of Formula IX with a derivatizing agent to form a compound of Formula X
[0177] wherein L1 is a leaving group;

[0177] ##STR00038## [0178] (g) reacting the compound of the Formula X
with a compound of Formula II (2-methyl-4-fluoro-5-hydroxy-indole) in
situ in the presence of the solvent used in step (f) to form the compound
of the Formula VIII:

[0178] ##STR00039## [0179] (h) isolating the compound of the Formula
VIII; and [0180] (j) removing R4 from the compound of the Formula
VIII to form the compound of the Formula XI or a salt thereof (for
example a potassium or sodium salt thereof);

[0181] and whereafter the compound of the Formula XI obtained in the form
of the free acid may be converted into a salt form and the compound of
the Formula XI obtained in the form of a salt may be converted into the
free acid or into the form of an alternative salt, if necessary.

[0182] When the derivatizing agent is a chlorinating, brominating or
iodinating agent the process step (f) could comprise: [0183] (f) reacting
the compound of the Formula IX with a suitable derivatizing agent in the
presence of a suitable base and a solvent selected from toluene and
anisole, wherein the reaction is carried out by: [0184] (f-1) adding a
mixture of the compound of the Formula IX and the base in the solvent to
a mixture of the derivatizing agent in the solvent at a temperature in
the range of from 60 to 110° C. over a period of about 60 minutes;
or [0185] (f-2) adding the derivatizing agent to a mixture of the
compound of the Formula IX and the base in the solvent at ambient
temperature over a period of about 15 minutes and then heating the
reaction mixture over a period of about 90 minutes to a temperature in
the range of from 70 to 90° C. and stirring the reaction mixture
at that is temperature for about 1 hour; or [0186] (f-3) adding the
derivatizing agent to a mixture of the compound of the Formula IX and the
base in the solvent at a temperature in the range of from 60 to
110° C. over a period of about 15 minutes,

[0187] The process of the fourth aspect of the invention is advantageous
in that it allows a compound of the Formula XI to be made in high purity
and high yield on a larger scale.

[0188] In this aspect of the invention, following the manufacture of the
compound of the Formula VIII in step (g), the compound is isolated and,
optionally, purified in step (h) of the process. The isolated compound of
the Formula VIII is then used in step (j) for manufacturing a compound of
the Formula XI, either immediately or following storage for an
appropriate period of time. The isolation of the compound of the Formula
VIII in step (h) is advantageous because it enables a broader choice of
methods for removing the R4 group from the compound of the Formula
VIII in step (j), for example compared to when this step is conducted in
situ.

Reaction Conditions for Process (i)

[0189] The step (j) may comprise any suitable steps or procedures for
removing R4 that are described in the literature and/or that are
known to the skilled person. Particular steps that would be of use would
provide high quality and high purity product. For example, in step (j)
when R4 is a benzyl group this may be removed by catalytic
hydrogenation, such as hydrogen gas and a suitable catalyst such as
palladium on carbon. The use of catalytic hydrogenation is advantageous
because it provides a highly efficient and mild method of removing the
benzyl group and because it allows for the efficient removal of
by-products from the waste stream.

[0190] The reaction of step (j) may be carried out at any temperature and
in any solvent suitable for the particular method of removal of the
benzyl group being used. For example with N-methylpyrrolidinone as
solvent at a temperature between 20 to 60° C.

[0191] In one aspect of the invention, following step (j) of the process,
the compound of the Formula XI is isolated and/or purified. Any suitable
steps or procedures for isolating and/or purifying the desired product
that are described in the literature and/or that are known to the skilled
person may be used. Particular steps that would be of use would provide
high quality and high purity product.

[0192] According to a fifth aspect of the invention, there is provided a
process for the manufacture of AZD2171:

##STR00040## [0193] from a compound of the Formula IX:

[0193] ##STR00041## [0194] wherein R4 is a protecting group.
[0195] which process comprises the steps of converting the compound of
the Formula IX to a compound of the Formula XI:

[0195] ##STR00042## [0196] by conducting a process as discussed above
in relation to the third or the fourth aspect of the invention; and
[0197] (k) reacting the compound of the Formula XI with a compound of the
Formula XII or a compound of Formula XIII

[0197] ##STR00043## [0198] wherein L2 is a leaving group and
X.sup.- is a suitable counter ion such as PF6.sup.(hexafluorophosphate), chloride, bromide, or tetraphenylborate; [0199] in
the presence of a suitable base to provide a compound of the Formula I
(AZD2171) or a salt thereof;

[0200] In one embodiment the compound of the Formula XII is provided as
the hydrochloride salt. In another embodiment the compound of Formula XII
is provided as the oxalate salt.

[0201] According to a further embodiment of the invention there is
provided an oxalate salt of a compound of Formula XII.

[0202] Example of L2 include chlorine, bromine, iodine, mesyloxy and
tosyloxy. In another embodiment example of L2 include chlorine,
bromine and iodine.

[0203] In one embodiment in step (k) the compound of Formula XI is reacted
with a compound of Formula XII. In another embodiment in step (k) the
compound of Formula XI is reacted with a compound of Formula XIII.

[0204] And thereafter the compound of the Formula I obtained in the form
of the free base may be converted into a salt form and the compound of
the Formula I obtained in the form of a salt may be converted into the
free base or into the form of an alternative salt, if necessary.

[0205] The process of the fifth aspect of the invention is advantageous in
that it allows the compound of the Formula I to be made in high purity
and high yield on a larger scale. Typically the process of the fifth
aspect of the present invention proceeds in greater than 80% yield. The
process of the fifth aspect of the invention is also advantageous for at
least the reasons discussed above in relation to the third and fourth
aspects of the invention.

[0206] In one embodiment the compound of the Formula XI is isolated and/or
purified before step (k) is conducted, for example using any suitable
steps or procedures that are described in the literature and/or that are
known to the skilled person as discussed above. In another embodiment the
compound of the Formula XI is reacted in-situ with a compound of Formula
XII or Formula XIII.

[0208] Step (k) may be conducted in any suitable solvent and at any
suitable temperature.

[0209] When the base used in step (k) is selected from sodium carbonate
and potassium carbonate, suitable solvents include, for example,
N-methylpyrrolidinone and N,N-dimethylformamide. In this aspect, step (k)
typically may be conducted at a temperature in the range of from 60 to
105° C., conveniently in the range of from 80 to 100° C.,
conveniently in the range of from 75 to 85° C.

[0210] The process of the fifth aspect of the invention is advantageous in
that it allows the AZD2171 to be made in high purity and high yield on a
larger scale. Typically, each of the steps of the process of the fifth
aspect of the present invention proceeds in greater than 80% yield.

[0211] According to a sixth aspect of the present invention, there is
provided a process for the manufacture of AZD2171 from a compound of the
Formula IX:

##STR00044## [0212] wherein R4 is a protecting group. [0213] which
process comprises the steps of: [0214] (f) reaction of a compound of
Formula IX with a derivatizing agent to form a compound of Formula X
[0215] wherein L1 is a leaving group;

[0215] ##STR00045## [0216] (g) reacting the compound of the Formula X
with 2-methyl-4-fluoro-5-hydroxy-indole, optionally in situ, optionally
in the presence of the solvent used in step (f), to form a compound of
the Formula VIII:

[0216] ##STR00046## [0217] (i) removing R4 from the compound of
the Formula VIII to form the compound of the Formula XI:

[0217] ##STR00047## [0218] (k) reacting the compound of the Formula XI
with a compound of the Formula XII or a compound of Formula XIII

[0218] ##STR00048## [0219] wherein L2 is a leaving group and
X.sup.- is a suitable counter ion such as PF6.sup.(hexafluorophosphate), chloride or bromide; [0220] in the presence of a
suitable base to provide a compound of the Formula I (AZD2171) or a salt
thereof;

[0221] whereafter the AZD2171 obtained in the form of the free base may be
converted into a pharmaceutically acceptable salt form, if necessary.

[0222] The process of the sixth aspect of the invention is advantageous in
that it allows the AZD2171 to be made in high purity and high yield on a
larger scale. Typically, each of the steps of the process of the seventh
aspect of the present invention proceeds in greater than 80% yield.

[0223] When the derivatizing agent is a chlorinating, brominating or
iodinating agent the process step (f) could comprise: [0224] (f) reacting
the compound of the Formula IX with a suitable derivatizing agent in the
presence of a suitable base and a solvent selected from toluene and
anisole, wherein the reaction is carried out by: [0225] (f-1) adding a
mixture of the compound of the Formula IX and the base in the solvent to
a mixture of the derivatizing agent in the solvent at a temperature in
the range of from 60 to 110° C. over a period of about 60 minutes;
or [0226] (f-2) adding the derivatizing agent to a mixture of the
compound of the Formula IX and the base in the solvent at ambient
temperature over a period of about 15 minutes and then heating the
reaction mixture over a period of about 90 minutes to a temperature in
the range of from 70 to 90° C. and stirring the reaction mixture
at that temperature for about 1 hour; or [0227] (f-3) adding the
derivatizing agent to a mixture of the compound of the Formula IX and the
base in the solvent at a temperature in the range of from 60 to
110° C. over a period of about 15 minutes,

[0228] Preferred aspects of the process of the sixth aspect of the
invention are as set out above in relation to individual steps as
described in the second, third, fourth and fifth aspects of the present
invention. In particular, preferred aspects of the process of the sixth
aspect of the invention are as set out above, for example, in relation to
individual steps of the third and fifth.

[0229] Conveniently, the base used in step (k) of the process of the sixth
aspect of the present invention is potassium carbonate and the suitable
solvent is N-methylpyrrolidinone.

[0230] The invention is illustrated hereinafter by means of the following
non-limiting examples in which, unless otherwise stated:

[0231] (i) evaporations were carried out by rotary evaporation in vacuo
and work-up procedures were carried out after removal of residual solids
such as drying agents by filtration;

[0232] (ii) yields are given for illustration only and are not necessarily
the maximum attainable;

[0245] tert-Butyl acetoacetate (3.852 g) was added to a stirred mixture of
sodium tert-pentoxide (2.804 g) in toluene (26 ml) at 40° C. The
mixture was heated to 70° C. and 1,2,3-trifluoro-4-nitrobenzene
(2.00 g) added. The mixture was maintained at 70° C. for 3 hours.
The mixture was cooled to 25° C. and 20% w/w sulphuric acid added
to adjust the mixture to pH 1. Sodium bicarbonate was added to bring the
mixture to pH 5. Water (5 ml) and saturated sodium chloride (5 ml) was
added. The lower aqueous layer was discarded and the organic layer is
washed successively with water (7 ml), water (7 ml), 2.3% w/w aqueous
sodium bicarbonate solution (2.75 ml) and then water (6 ml). The organic
layer was distilled under reduced pressure (50 mbar), to leave a solution
of tert-butyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in toluene.

[0246] A small amount was vacuum distilled at 100° C., 0.4 mbar to
give a purified sample of tert-butyl
2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate

[0252] To a solution of tert-butyl
2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate (7.89 g) in
dichloromethane was added trifluoroacetic acid (11.2 g) and the mixture
stirred at ambient temperature for 20 hours. The mixture was concentrated
to a thick paste and toluene (14 ml) added and the mixture distilled on a
rotary evaporator (77 mbar, bath 40° C.). Further toluene (14 ml)
was added and the mixture distilled. Sodium hydroxide (7.4% w/w, 20 ml)
was added and the lower aqueous layer separated and washed with toluene
(18 ml). The aqueous layer was diluted with water (20 ml) and warmed to
40° C. Acetic acid (13 ml) was added followed by sulphuric acid
(20% w/w, 20 ml). The mixture was cooled to 0° C. and further
water (43 ml) added. The mixture was cooled to -5° C. and left
overnight. The solid was filtered and washed with water (24 ml). The
solid was dried in a vacuum oven to give
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1.65 g, 30.7%).

[0255] 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (1 g) was
dissolved in a solution of potassium carbonate (1.3 g) in water (13 ml).
A solution of sodium dithionite (5.24 g) in water (12.3 ml) was added
dropwise. The mixture was stirred for 1.5 hours, then left to stand
overnight. The solid was filtered and washed with water (6 ml). The solid
was dried at 35° C. in a vacuum oven to give crude
4-fluoro-2-methyl-1H-indol-5-ol (0.5 g, 64.5%).

[0256] The crude solid (250 mg) was dissolved in dichloromethane (6.75 ml)
and filtered through a pad of silica (250 mg). The filter pad was washed
with dichloromethane (3.4 ml). The combined filtrates were distilled,
removing 6 ml of dsitillate. The concentrate was then added dropwise to
isohexane (4.25 ml) and the mixture concentrated, removing 3 ml of
distillate. The mixture was cooled in an ice-bath and the precipitate
filtered and washed with isohexane (0.9 ml). The solid was dried in a
vacuum oven at 35° C. to give 4-fluoro-2-methyl-1H-indol-5-ol (180
mg, 72%)

[0260] The solution of tert-butyl
2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate from above was extracted
with 40% w/w aqueous Triton B (164 kg, 1.10 eq). To the aqueous phase was
added further 40% w/w Triton B (298 kg, 2.0 eq) followed by sodium
hydroxide (97 kg, 6.8 eq). The solution was heated at 50° C. for
18 hours. The mixture was cooled to 25° C. and water (392 kg)
added followed by 20% w/w sulphuric acid (664 kg) and then
dichloromethane (187 l). Further 20%w/w sulphuric acid was added until
the mixture was pH 5. The organic layer was separated and the aqueous
layer further extracted with dichloromethane (187 l). The combined
organic layers were distilled under reduced pressure (500 mbar), removing
160 kg of distillate to give tert-butyl
2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate as a solution in
dichloromethane.

[0261] To tert-butyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate
in dichloromethane from above was added further dichloromethane (123 l)
followed by trifluoroacetic acid (158 kg) whilst maintaining the
temperature at 25° C. The reaction was stirred for 20 hours. The
mixture was distilled, removing 283 kg of distillate. Toluene (176 l) was
added and the mixture distilled, removing 208 kg of distillate. Further
toluene (176 l) was added and the mixture distilled, removing 133 kg of
distillate. To the residue was added 7.4% w/w aqueous sodium hydroxide
(˜705 kg) until the mixture was pH 10.5. The aqueous layer was
separated and washed with toluene (250 l). The aqueous layer was diluted
with water (250 l), heated to 40° C. and acetic acid (191.4 kg)
added, reducing the pH from 10.1 to 3.8. The pH was then adjusted to 1
with 20% w/w sulphuric acid (˜315 kg). The mixture was cooled to
0° C. and seeded with
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one. Further water (600 kg)
was added and the solid isolated by filtration. The filter cake was
washed with water (300 l). The product was dried under vacuum (50 mbar)
at 40° C. Yield: 56.0 kg, 74% based on
1,2,3-trifluoro-4-nitrobenzene.

Preparation of 4-fluoro-2-methyl-1H-indol-5-ol (Large Scale)

[0262] To a solution of potassium carbonate (79 kg) in water (800 kg) was
added 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (61 kg) and the
mixture stirred to give a solution. To this solution at 25° C. was
added a solution of sodium dithionite (298 kg) in water (750 kg). The
mixture was held at 25° C. for 2 hours. The product was isolated
by filtration, washing the filter cake with water (366 kg). The product
was dried under reduced pressure (50 mbar) at 35° C. Yield: 34 kg,
72%.

[0263] The crude 4-fluoro-2-methyl-1H-indol-5-ol (33 kg) was dissolved in
dichloromethane (880 l) and filtered through silica (33 kg). The filter
was washed with dichloromethane (440 l). The combined filtrates were
distilled, removing 835 l of distillate. This concentrate was added
rapidly to isohexane (360 kg), resulting in a suspension. The batch was
distilled, removing 436 l of distillate. The batch was cooled to
0° C., aged for 1 hour and then filtered. The filter cake was
washed with isohexane (73 kg). The product was dried under reduced
pressure (50 mbar) at 35° C. Yield: 31 kg, 68% based on
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one.

Example 3

Preparation of 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from
methyl acetoacetate

Preparation of Methyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate

[0264] Sodium tert-pentoxide (13.41 g) was added to mesitylene (112 ml)
and the slurry heated to 50° C. to give a red/brown solution. To
this was added methyl acetoacetate (14.28 g). The mixture exothermed to
75° C., giving a thick orange/yellow slurry. The temperature was
adjusted to 70° C. and 1,2,3-trifluoro-4-nitrobenzene (10.0 g)
added, giving an orange solution. The mixture was maintained at about
70° C. for 3 hours, then allowed to cool to ambient and left
overnight. To the mixture was added hydrochloric acid (6% w/w, 43 ml).
The lower aqueous layer was separated and the organic layer further
washed twice with hydrochloric acid (6% w/w, 36 ml). The organic layer
was washed with aqueous sodium bicarbonate solution (2.3% w/w, 15 ml) and
then water (30 ml). Further mesitylene (21 ml) was charged and the
mixture evaporated on a rotary evaporator (25 mbar, bath 40° C.),
giving 25 ml of solution.

[0265] A small amount of this solution (5 ml) was concentrated (68°
C., 10 mbar) to give methyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate
(2.22 g) as a yellow/brown oil.

[0268] To a solution of methyl
2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in mesitylene (11.01 g, 20
ml of solution) was added Triton B (40% w/w, 50.54 g). The separation was
poor so further mesitylene (8 ml) was added. The lower aqueous layer was
separated and 5 further Triton B (40% w/w, 50.54 g) added to it. The
aqueous mixture was held at 55° C. for 16 hours. The mixture was
cooled to ambient and hydrochloric acid (32% w/w, 19 ml) added over 15
minutes until the pH was 5. Dichloromethane (24 ml) was added and the
lower organic layer separated. The aquous layer was further extracted
with dichloromethane (24 ml) and the combined organic phase basified by
the addition of aqueous sodium hydroxide (8.5% w/w, 23 ml) to pH 10.5.
The aqueous phase was further washed with isohexane (23 ml), to give an
aqueous solution of methyl
2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate.

[0269] A small amount was evaporated to dryness on a rotary evaporator to
give a sample for analysis.

[0272] Water (17.7 ml) was added to acetic acid (15.6 ml) followed by
sulphuric acid (16.6 ml). To this solution was added an aqueous solution
containing methyl 2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate
(8.195 g) and the mixture heated at 90° C. for 4 hours. The
mixture was cooled to 80° C. and water (24.6 ml) added. The mature
was cooled to 40° C. and a seed of
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (2 mg) added. The
mixture was cooled to 0° C. and left to stir overnight. The solid
was filtered, washed three times with water (15 ml) and dried under
vacuum at 40° C. to give
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (320 mg,)

Preparation of 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one from
ethyl acetoacetate

Preparation of Ethyl 2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate

[0275] Sodium tert-pentoxide (33.52 g) was added to mesitylene (280 ml)
and the mixture heated to 50° C. To the suspension was added ethyl
acetoacetate (39.61 g) over 10 minutes. The reaction mixture exothermed
to about 60° C. The thick slurry was heated to 70° C. and
1,2,3-trifluoro-4-nitrobenzene (25.0 g) added. The mixture exothermed to
80° C. The mixture was held at 70-80° C. for 3 hours, then
allowed to cool to ambient and left overnight. To the mixture was added
hydrochloric acid (6% w/w, 100 ml), until the pH reached 1. The aqueous
layer was separated and discarded and the organic layer washed twice with
hydrochloric acid 6% w/w, 90 ml), then with aqueous sodium bicarbonate
(2.3% w/w, 37.5 ml) and finally water (75 ml). To the organic layer was
added further mesitylene (53 ml) and the mixture distilled on a rotary
evaporator (10 mbar, bath 60° C.) to give a solution of ethyl
2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate in mesitylene (90 ml
containing 36.22 g of ethyl
2-(2,3-difluoro-6-nitrophenyl)-3-oxobutanoate).

[0276] A small sample (10 ml) was further evaporated on a rotary
evaporator (12 mbar, bath 60° C.)

[0282] To a mixture of acetic acid (57 ml) and water (68 ml) was added
sulphuric acid (61 ml). The mixture was warmed to 97° C. and an
aqueous solution containing ethyl
2-(2-fluoro-3-hydroxy-6-nitrophenyl)-3-oxobutanoate (31.6 g) added. The
mixture was heated at 97° C. for 3.5 hours, then cooled to
80° C. and water (95 ml) added. The mixture was cooled to
40° C. and seeded with
1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (2 mg). The mixture was
cooled to 0° C. and stirred overnight. The mixture was filtered
and washed three times with water (58 ml). The product was dried in a
vacuum oven to give 1-(2-fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one
(8.42 g, 35.7%).

[0285] 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (28 kg) and
triethylamine hydrochloride (2.7 kg) were added to anisole (244 kg).
N,N-Diisopropylethylamine (19.2 kg) was added, followed by a line wash of
anisole (20 kg). The mixture was cooled to 15° C. and phosphorus
oxychloride (19.8 kg) added over 5 minutes, followed by a line wash of
anisole (13.9 kg). After stirring for 15 minutes the mixture was heated
to 80° C. over 90 minutes and held at 80° C. for 1 hour.
When the reaction was complete the batch was transferred to a new
reactor, followed by a line wash of anisole (39.7 kg). The mixture was
cooled to 40° C. and 16.19% w/w aqueous sodium hydroxide solution
(132 kg) added over 15 minutes, allowing the temperature to rise to
50° C., followed by a line wash of water (5 kg). The mixture was
held at 50° C. for 30 minutes, then heated to 80° C. The
batch was filtered through a Gaf filter, followed by a line-wash of
anisole (10 kg). The lower aqueous layer was separated and the upper
organic layer washed at 80° C. with 20.9% w/w aqueous sodium
chloride solution (98.2 kg). The mixture was distilled under reduced
pressure (80 mbar) to leave a residual volume of 224 l.
1-Methyl-2-pyrrolidinone (28.9) was added and the mixture heated to
80° C. to give a solution of
7-(benzyloxy)-4-chloro-6-methoxyquinazoline.

[0286] 4-Fluoro-2-methyl-1H-indol-5-ol (17.2 kg) was dissolved in
acetonitrile (85 kg). The solution was degassed by holding under vacuum
(150 mbar) and then pressurising to 21.6 bar with nitrogen. This was
carried out four times. The solution was cooled to 0° C. and a
16.19% w/w aqueous sodium hydroxide solution (25.7 kg) added over 15
minutes, maintaining the temperature at 0° C., followed by a line
wash of acetonitrile (3 kg). This cold solution was is added over 45
minutes to the solution of 7-(benzyloxy)-4-chloro-6-methoxyquinazoline at
80° C., followed by a line wash of acetonitrile (22 kg). The
mixture was held at 80° C. for 4 hours, then washed twice with
water (42 kg). The mixture was cooled to 20° C. and distilled
under reduced pressure (250 mbar) until the batch temperature reached
70° C. The vacuum was then adjusted to 80 mbar and the
distillation continued to a residual volume of 168 l. The batch was
cooled to 65° C. and a solution of water (56 kg) in methanol (133
kg) added, maintaining the temperature at 60-65° C. The mixture
was cooled to 20° C. over 1 hour, then held at 20° C. for 2
hours. The product was isolated by filtration, washing the cake twice
with methanol (33 kg). The product was dried with nitrogen at 40°
C. Yield: 32.7 kg, 77%.

[0289] The 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one starting
material was prepared as follows:

[0290] A mixture of vanillic acid (200 g), acetonitrile (600 ml) and
N-ethyldiisopropylamine (580 ml) was heated to reflux. Benzyl bromide
(347 ml) was then added over a period of 3 hours. The reaction mixture
was held at reflux for 15 hours. Triethylamine (50 ml) was added and the
reaction mixture held at reflux for a further 30 minutes. Acetonitrile
(400 ml) was added and the reaction mixture heated to 81° C. Water
(300 ml) was added and the reaction mixture cooled to 45° C. The
reaction mixture was held at 45° C. for 30 minutes until
crystallisation occurred. The reaction mixture was then allowed to cool
to 24° C. and then further cooled to 8° C. and the product
(benzyl 4-(benzyloxy)-3-methoxybenzoate) isolated by filtration. The
solid was washed with water (3×500 ml) and then dried under vacuum
at 45° C. Yield: 387 g, 93.4%

[0293] Benzyl 4-(benzyloxy)-3-methoxybenzoate (78 g) was mixed with
dichloromethane (580 ml), water (72 ml) and glacial acetic acid (288 ml).
The mixture was cooled to 10° C. Concentrated sulfuric acid (108
ml) was added in a controlled manner maintaining the temperature of the
reaction mixture below 25° C. Concentrated nitric acid (17.5 ml)
was then added keeping the temperature of the reaction mixture below
20° C. The reaction mixture was then stirred at 20° C. for
23 hours. The lower aqueous layer was removed and the organic layer was
washed with water (290 ml). The organic layer was separated and distilled
to 270 ml at atmospheric pressure. Isopropanol (750 ml) was added to the
reaction mixture at 45° C. The reaction mixture was then heated to
40° C. and stirred at this temperature for 15 minutes. The
resulting suspension was then cooled to 20° C., then to 5°
C. and held at this temperature for one hour. The product (benzyl
4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration,
washed with isopropanol (200 ml) and dried at less than 25° C.
Yield: 78.4 g, 89.6%;

[0296] Benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate (77 g) was dissolved
in acetonitrile (882 ml). Sodium dithionite (160.5 g) was added to the
solution and the temperature adjusted to 25° C. Water (588 ml) was
then added, maintaining the temperature at 25° C. The pH was
maintained at 6 using 8.8 M sodium hydroxide during the reduction. The
slurry was then heated to 65° C. and the lower aqueous phase was
removed. Concentrated hydrochloric acid (35% w/w, 7.25 ml) was then
added. The slurry was allowed to cool to 40° C. and then to
20° C. Sodium hydroxide solution (47% w/w, 12.4 ml) was added and
the slurry cooled to 0° C. The product (benzyl
2-amino-4-(benzyloxy)-5-methoxybenzoate) was isolated by filtration,
washed with water (2×196 ml) and then dried at 40° C. under
vacuum. Yield: 66.2 g, 92.4%;

[0299] Benzyl 2-amino-4-(benzyloxy)-5-methoxybenzoate (5.55 kg),
formamidine acetate (2.2 kg) and isobutanol (33.3 L) were mixed. The
reaction mixture was then heated to 97° C. and stirred at this
temperature for 6 hours. The reaction mixture was then cooled to
25° C. over a period of at least an hour and then stirred at this
temperature for 30 minutes. The product
(7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one) was isolated by
filtration, washed with isobutanol (6.1 L) and dried in the vacuum oven
at a temperature of from 40 to 45° C.

[0303] 7-(Benzyloxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyqui-
nazoline (40 kg) was dissolved in 1-methyl-2-pyrrolidinone (206 kg) at
40-45° C. This solution was charged to an inerted pressure vessel
containing 10% palladium on carbon catalyst (0.235 kg of approximately
50% water wet catalyst). A line wash of 1-methyl-2-pyrrolidinone at
40-45° C. (35 kg) was applied. The mixture was hydrogenated at
45° C. and 3 barg for 3.5 hours. The reactor was purged with
nitrogen and recirculated through a Gaf filter before being filtered
through a 1 μm Pall filter into a new reactor. A line wash of
1-methyl-2-pyrrolidinone (66 kg) through the filters was applied to give
a solution of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol. To
this solution was added potassium carbonate (10.3 kg) and the mixture
heated to 80° C.

[0305] The solution of 1-(3-chloropropyl)pyrrolidine in methyl tert-butyl
ether was added to the hot solution of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol in
1-methyl-2-pyrrolidinone. A line wash of methyl tert-butyl ether (4 kg)
was applied. The mixture was maintained at 80° C. for 3 hours,
then water (348 kg) was added over 2 hours. The suspension was cooled to
60° C. over 4 hours and held at 60° C. for 12 hours. The
product was isolated by filtration and the cake washed with 1:1 w/w
1-methyl-2-pyrrolidinone/water (64 kg), then three times with water (62
kg). The product was dried with hot nitogen at 45° C.

[0309] The aqueous 1-(3-chloropropyl)pyrrolidine hydrochloride solution
was prepared as follows:

[0310] A solution of 1-bromo-3-chloropropane (99.5 kg) in toluene (237 kg)
was heated to 40-45° C. To this solution was added pyrrolidine
(94.5 kg) over 1.5 hours, maintaining the temperature at 40-45° C.
A line wash of toluene (37 kg) was applied and the reaction maintained at
40-45° C. for a further four hours. The reaction mixture was
cooled to 20-25° C. and washed with water (211 kg). Further water
(138 kg) was added and the pH adjusted to 8.8-9.0 by the addition of 34%
w/w hydrochloric acid (4.7 kg). The aqueous phase was separated and
discarded. To the organic phase was added 34% w/w hydrochloric acid (61
kg) until the pH was 0.5-1.0. The aqueous was separated and concentrated
under vacuum, maintaining the temperature <50° C. until the
toluene content was <0.1%, giving an aqueous solution of
1-(3-chloropropyl)pyrrolidine hydrochloride 129.1 kg at 71.5% w/w, 79.9%

[0313] 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(pyrrolidin-
-1-yl)propoxy]quinazoline can be similarly prepared by using a methyl
tert-butyl ether solution of 1-(3-chloropropyl)pyrrolidine prepared from
1-(3-chloropropyl)pyrrolidine oxalate.

[0314] 1-(3-Chloropropyl)pyrrolidine oxalate (134.8 kg) was suspended in
water (226 l) and methyl tert-butyl ether (83.4 kg) added. The stirred
mixture was basified to pH>11 by addition of 49% w/w aqueous potassium
hydroxide solution (138.9 kg). A line wash of water (22.6 l) was applied.
The lower aqueous layer was separated and transferred to a second
reactor. The upper organic layer was transferred to 200 l drums. A line
wash of methyl tert-butyl ether (16.7 kg) was applied. The aqueous layer
was recharged to the original reactor and further extracted with methyl
tert-butyl ether (83.4 kg). The lower aqueous layer was discarded. The
original oraganic layer was recharged from the drums. A line wash of
methyl tert-butyl ether (16.7 kg) was applied. The combined organic
layers were washed with 23% w/w aqueous potassium chloride solution (64.8
kg) to give a solution of 1-(3-chloropropyl)pyrrolidine (83.9 kg) in
methyl tert-butyl ether. The required amount of solution can then be used
as appropriate.

[0315] 1-(3-Chloropropyl)pyrrolidine oxalate was prepared as follows:

[0316] To a solution of 1-bromo-3-chloropropane (190 g) in toluene (455
ml) at 40° C. was added pyrrolidine (173 g), maintaining the
temperature at 40-45° C. A line wash of toluene (40 ml) was then
applied. The mixture was maintained at 40-45° C. for 4 hours, then
cooled to 20° C. and held for 6 hours. The mixture was washed with
water (400 ml), and then further water (265 ml) added and the pH adjusted
to 8.8-9.0 with extracted with 37% hydrochloric acid (9.5 ml). The
aqueous layer was separated.

[0317] The organic layer was added to a solution of oxalic acid dihydrate
(129.31 g) in a mixture of isopropanol (1070 ml) and water 109 ml) over 1
hour at 65-70° C. The mixture was cooled to 55° C. and held
at this temperature for 30 minutes to initiate crystallisation. The
mixture was then cooled to 10° C. over 1.5 hours, and held at
10° C. for an hour before filtering. The solid was washed with
methyl tert-butyl ether (400 ml) and finally methyl tert-butyl ether (300
ml). The solid was dried at 40° C. in a vacuum oven to give
1-(3-chloropropyl)pyrrolidine oxalate.

[0320] 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin--
1-ylpropoxy)quinazoline (28.4 kg at 100% w/w) was suspended in methanol
(284 l). The mixture was degassed by holding under vacuum (-0.7 barg),
then releasing the vacuum with nitrogen. This was carried out three
times. The slurry was heated to reflux to give a clear solution. The
solution was cooled to 60° C. and recirculated through a Gaf
filter, before being filtered through a 1 μm Pall filter into the
crystalliser. A line wash of methanol (85 l) was applied, after being
degassed as before.

[0321] Methanol (114 l) was cooled to 0° C. and degassed as above.
Maleic acid (6.96 kg) was added and the mixture stirred to give a clear
solution whilst maintaining the temperature at 0° C. This was
transferred via a 1 μm Pall filter to the crystalliser, maintaining
the temperature in the crystalliser at 55-60° C. A line wash of
methanol (43 l) was applied. The temperature was adjusted to 55°
C. and micronised
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpr-
opoxy)quinazoline maleate salt (Form A, 0.43 kg) was added. The mixture
was held at 55° C. for 3 hours, then cooled to 40° C. over
7 hours, then cooled to -5° C. over 6 hours. The suspension was
held at -5° C. for 20 hours. The product was isolated by
filtration, washing the cake with methanol (128 l). The product was dried
under hot nirogen at 50° C. Yield: 27.3 kg, 76%

[0324] 1-(3-Chloropropyl)pyrrolidine (1.142 g) was dissolved in methanol
(38 ml) and the solution refluxed overnight. The solution was evaporated
to dryness on a rotary evaporator to give 4-azoniaspiro[3,4]octane
chloride as an impure oil.

[0328] An aqueous solution of 4-azoniaspiro[3,4]octane chloride was
prepared by adding 1-(3-Chloropropyl)pyrrolidine (128 ml) to water (100
ml) at 94° C. over 25 minutes. The mixture was stirred for a
further 5 minutes to give a clear yellow solution. This was cooled to
20° C. and stored in a bottle. Line washes of water (2×25
ml) were applied.

[0329] 4-Azoniaspiro[3,4]octane chloride solution in water (88 ml) was
added over 10 minutes to a solution of sodium hexaflurophosphate (50.3 g)
in water (100 ml), followed by a line wash of water (12 ml). Further
water (50 ml) was added to aid stirring of the thick suspension. The
mixture was heated to 90° C. to aid stirring. The solid was
filtered and washed with water (2×100 ml) and dried in a vacuum
oven to give 4-azoniaspiro[3,4]octane hexafluorophosphate (54.14 g, 70.3%
of theory).

[0335] 1,3-dibromopropane (287 ml) was heated to 45° C. and
pyrrolidine (23.4 ml) added over 4 hours. The mixture was then cooled to
room temperature and evaporated to dryness on a is rotary evaporator. To
the residual oil was added water (200 ml) and the small organic lower
layer separated. The solution was washed with dichloromethane (20 ml).
The aqueous layer was basified by the addition of potassium carbonate
(42.8 g) and extracted with dichloromethane (2×80 ml). The combined
organic extracts were dried over magnesium sulphate and evaporated to
dryness on a rotary evaporator. The residue was triturated by the
addition of acetone (30 ml) and stirred overnight. The solid was
filtered, washed with acetone (30 ml) and dried in a vacuum oven at
40° C.

[0339] 4-Azoniaspiro[3,4]octane chloride (1.14 g) was added to a mixture
of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol (2.5
g), 1-methyl-2-pyrrolidinone (25 ml), methyl tert-butyl ether (1.8 ml)
and potassium carbonate (815 mg) at 80° C. After stirring at
80° C. for 3 hours water (27 ml) was added over 40 minutes. The
mixture was allowed to cool to 20° C. and left overnight. The
mixture was reheated to 60° C. and filtered. The filter cake was
washed with 1:1v/v 1-methyl-2-pyrrolidinone/water (5 ml) and then with
water (4×5 ml). The solid was dried in a vacuum oven to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpr-
poxy)quinazoline.

[0341] To a solution of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol (2.5 g)
in 1-methyl-2-pyrrolidinone (25 ml) and methyl tert-butyl ether (1.8 ml)
was added potassium carbonate (815 mg). The mixture was degassed by
holding under vacuum and letting down with nitrogen. This was carried out
five times. The mixture was heated to 80° C. and
4-azoniaspiro[3,4]octane bromide (1.75 g) was added. The mixture was
maintained at 80° C. for 3.5 hours. To the hot mixture was added
water (27 ml) over 2 hours. The mixture was cooled to 64° C. and
the solid filtered. The solid was washed with 1:1 v/v
1-methyl-2-pyrrolidinone/water (5 ml) and then water (4×5 ml). The
solid was dried in a vacuum oven to give
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1-ylpr-
poxy)quinazoline.

[0345] 1-(2-Fluoro-3-hydroxy-6-nitrophenyl)-propan-2-one (4.286 g) was
suspended in acetonitrile (16 ml) and cooled to -5° C. To the
slurry was added aqueous sodium hydroxide (0.93 ml of 46.9% w/w
solution). A line wash of acetonitrile (16 ml) was applied.

[0346] This cold solution was added to a solution of
7-(benzyloxy)-4-chloro-6-methoxyquinazoline (4.26 g) in anisole (28.8 ml)
at 80° C. over 15 minutes. A line wash of acetonitrile (16 ml) was
applied. The mixture was heated at 80° C. for 21 hours. The
stirrer was stopped and the lower aqueous layer separated. The upper
organic layer was washed further with water (6 ml) at 80° C.

[0347] The batch was cooled to 20° C. and concentrated under
reduced pressure (130 mbar), allowing the batch temperature to reach
100° C., collecting 24 ml of distillate. The batch temperature was
adjusted to 65° C. and a solution of water (4 ml) in methanol (28
ml) added. The mixture was cooled to 20° C. and the product
filtered. The filter cake was washed with methanol (2×12 ml) and
dried in a vacuum oven at overnight to give
1-(3-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]oxy}-2-fluoro-6-nitrophenyl-
)acetone (4.543 g, 67% of theory).

[0350] To a solution of
1-(3-{[7-(benzyloxy)-6-methoxyquinazolin-4-yl]oxy}-2-fluoro-6-nitrophenyl-
)acetone (0.75 g) in 1-methyl-2-pyrrolidinone (7.5 ml) was charged 10%
palladium on charcoal catalyst (38.6 mg of approximately 50% water wet
paste). The mixture was warmed to 50° C. and hydrogenated under 4
bar atmosphere of hydrogen for 2.75 hours. This gave a solution
containing 28% peak area of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol.

[0351] Hplc retention time of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol 12.36
mins. This was identical to the retention time of
4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-ol as
prepared in Example 6.